| In Vitro | In vitro activity: AS 602801 (AS602801) treatment induces cell death and accordingly decreased the number of viable cells in all three cell lines in a dose-dependent manner, suggesting that AS 602801 may have selective cytotoxic activity against neoplastic cells. AS 602801 exhibits cytotoxicity against both serum-cultured non-stem cancer cells and cancer stem cells derived from human pancreatic cancer, non-small cell lung cancer, ovarian cancer and glioblastoma at concentrations that did not decrease the viability of normal human fibroblasts. AS 602801 also inhibits the self-renewal and tumor-initiating capacity of cancer stem cells surviving AS 602801 treatment.
Kinase Assay: AS602801 (also known as Bentamapimod and PGL5001) is a novel, potent and ATP-competitive JNK (c-Jun N-terminal Kinase) inhibitor with IC50 values of 80 nM, 90 nM, and 230 nM for JNK1, JNK2, and JNK3, respectively. It acts as a JNK inhibitor which could reduce the surface and volume of induced endometriosis in the baboon without any significant effect on cycle length or serum reproductive hormones, and without significant endocrine side effects.
Cell Assay: PANC-1, A2780, and A549 human cancer cells and IMR90 human normal fibroblasts are treated without (control) or with the indicated concentrations of AS 602801 (2.5, 5, and 7.5 μM) for 3 days. The number of viable cells (left panels) and the percentage of dead cells (right panels) are determined using trypan blue as a vital dye. |
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| In Vivo | Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS 602801 (AS602801) causes 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS 602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS 602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS 602801 alone or MPA + AS 602801 suppresses MMP-3 production. In an autologous rat endometriosis model, AS 602801 causes 48% regression of lesions compared to GnRH antagonist Antide (84%). AS 602801 reduces inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns are unaffected. Furthermore, AS 602801 enhances natural killer cell activity, without apparent negative effects on uterus. |
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